Transcript lect6(101503)

Lecture 6:
Study Design I: Clinical Trials
Reading
Gordis - Chapters 6, 7
Lilienfeld and Stolley - Chapters 8, 9
Types of studies
• Experimental: randomized clinical trials
• Non-experimental (observational):
– Prospective (cohort) studies
– Retrospective (case-control) studies
Objectives of randomized trials
• Evaluate therapeutic and preventive aspects
of medical practice
• Evaluate new approaches to health care
delivery
• Evaluate impact of health education on health
behavior
Design of a randomized trial
Reference population
Study Population
RANDOMIZATION
New Treatment
Improved
Not
Improved
Current Treatment
Improved
Not
Improved
Randomized control trials (RCT)
• RCT are generally regarded as the most
scientifically rigorous method of hypothesis
testing available in epidemiology.
• RCT have greatest control over the research
setting
– manipulation of study factor
– random assignment of exposure
Reference population
Study Population
RANDOMIZATION
New Treatment
Improved
Not
Improved
Current Treatment
Improved
Not
Improved
Considerations in selecting a
study population
• Source (reference) population: the population
for whom the results of the intervention are
thought to be applicable.
• Target (study) population: the group in which
the intervention is conducted
• Our objective is to generalize the results
beyond the study population
Considerations in selecting a
study population
• Internal validity is the ability to reach the
correct conclusion in those actually studied
– Absence of methodologic problems in the
study
• External validity is the generalizability of the
study to the reference population
– Do studies of physicians REALLY
represent the general population?
Source
population
Eligible
Study
population
Ineligible
Decline
participation
Consent to
participate
Random Allocation
New Treatment
Current Treatment
Subject selection: factors to consider in
setting eligibility criteria
1. Potential benefits and risks of intervention(s)
a. Who would be expected to reap benefits
from the new intervention?
b. For whom would the new intervention
pose unacceptable risks? (Example:
known allergy).
2. Need to think proactively about internal
validity of trial
a. Ability of subjects to provide valid and
reliable data: e.g., intact mental status,
language fluency
b. Expected compliance with a regimen.
c. Low probability of dropping out: e.g.,
expectation of continued residence in
community, absence of serious
comorbidity.
3. Enhancement of the power of the trial
a. May restrict participation to a group with
known high incidence of relevant
outcome(s).
b. May restrict to a relatively homogeneous
study population, in order to reduce
variability in outcome.
c. May use matching to reduce variability in
outcomes from sources other than
exposure.
“Controlled trial of sotalol for one
year after myocardial infarction”
Julian et al.(1982) Lancet 1: 1142-47
• A multicenter (25) double-blind randomized
study.
• Treatment: 320 mg sotalol once daily
compared to placebo in patients surviving
acute myocardial infarction (MI)
• Patients between the ages of 30 and 69
years who had survived for five days after MI
were evaluated for inclusion
• Treatment started 5-14 days after infarction
• Subjects were excluded (55% of those
eligible for the study) for the following
reasons:
– heart block of >1st degree
– heart rate < 54 per minute
– women of child bearing years
– history of asthma or obstructive airway
disease
– IDDM
– clinical evidence of infarction at 12th postinfarction day
Julian et al.(1982) Lancet 1: 1142-47
• MORE exclusions!
– Systolic BP persistently < 100 mm Hg
– other cardiac or non-cardiac conditions
thought to be serious enough to worsen
short term diagnosis
– lack of cooperation by patient or inability to
follow up the patient for psychological or
geographical reasons (!)
Julian et al.(1982) Lancet 1: 1142-47
Source
population
Eligible
Study
population
Ineligible
Decline
participation
Consent to
participate
Random Allocation
New Treatment
Current Treatment
Informed Consent
By federal regulations this means subjects must
be told:
1. That they would be participating in research
2. The research procedures involved.
3. The potential risks and discomfort
4. The potential benefits (including those to
society)
5. Alternative procedures of possible
advantage to subjects
Informed Consent
And that’s not all….
6. Extent to which information gathered will
remain confidential
7. Medical services available in the event of an
injury, if more than minimal risk involved.
8. Whom to contact with questions about
research.
9. Voluntary nature of participation and right to
withdraw without penalty or loss of benefits
Source
population
Eligible
Study
population
Ineligible
Decline
participation
Consent to
participate
Random Allocation
New Treatment
Current Treatment
Randomization
• Randomization:
– Equal probability of participants to be
assigned to intervention or control group
– This is the basis for statistical inference
• By randomly assigning the treatment - reduce
the risk of confounding because:
“confounders - known and unknown” are
randomly distributed among the treatment
groups
• By blinding (masking) assessment of
outcome - reduce the risk of information bias
Methods of randomization:
simple random allocation
• Subjects assigned on entry to a treatment
group based on some pre-determined
allocation plan
– table of random numbers
– flipping a coin
• If the study is small, this method MAY result
in differences in group size or composition by
chance
Methods of randomization:
stratified randomization
• Randomization increases the likelihood of
comparability, but does not guarantee it
• Stratify by variables that are known to be
important (such as age) and randomize within
each strata
• Guarantees groups are comparable with
regard to the important variable
Example: stratified randomization
1,000 Patients
400
females
600
males
360 young
Stratify by sex
240 old
300 young
Stratify
by age
100 old
180 + 120+ 150 + 50
180 + 120 + 150 + 50
= 500
= 500
New treatment
Current treatment
How would an investigator know if the
randomization procedure was
successful?
Check baseline characteristics between the two
groups. For example,
Sotalol group
54% male
95% Caucasian
mean age = 54.5
Placebo group
53% male
96% Caucasian
mean age = 55.2
Blinding
• Blinding is when the observers and/or
subjects are kept ignorant as to the group to
which the subjects are assigned
• Single blind = subjects are ignorant
• Double blind = observer and subject are
ignorant
• Triple blind = observer, subject and analyst
are ignorant
Why use blinding?
• Use blinding to eliminate the effect of
knowledge of treatment- this introduces bias
– If a patient is aware of assignment,
knowledge of therapy may affect outcome
(use a placebo)
– Observer may differentially recognize and
record information regarding the patient
based on the treatment group of the
subject
What are typical comparison or
control groups in RCTs?
1. Placebo
a. A biologically inert intervention which is
used to elicit any non-specific
psychological effects of the test
intervention.
b. Designed to resemble the test
intervention as closely as possible,
except for the presumably active
component.
2. Using a specific alternative intervention
a. For example, comparing Vaccine A
versus Vaccine B.
b. Sometimes used to test a hypothesis of
equal efficacy (or bioequivalence),
possibly comparing a new intervention to
the best existing alternative.
3. “Usual care” comparison group
a. Used chiefly in trials that are
investigating methods of health care
delivery or health education.
b. Requires careful attention to what is
actually provided to the control group, so
that findings are interpretable.
Sample size in clinical trials
• How many people do we have to study to
obtain a statistically significant difference
between the groups?
• Sample size is calculated before the study
starts.
• Calculate the number that guarantees the
power (1-) of the study.
– See Gordis pp 110-115 for details
Planned crossover
Group 1
Group 2
Group 1
Group 2
Group 2
Group 1
Planned crossover
• Each patient can serve as his/her own
control, thus holding constant the variation
between individuals.
• Cautions:
– Carryover effects: need a washout period
to eliminate the effect from one treatment
to another.
– Order of treatments: may because of
psychological responses
– Not feasible for some treatments, e.g.,
surgery
Unplanned crossover
Original design
Randomized
Surgical
care
Medical
care
Reality
Randomized
Surgical
care
Medical
care
Refused
surgery
Require
surgery
Surgery
No
surgery
Unplanned crossover
• Analyze the unplanned crossover: intention to
treat- according to the original randomized
assignment.
Noncompliance (dropout)
• Patients may agree to be randomized, but
they may not comply with the assignment
treatment.
• The effect of noncompliance will be to reduce
observed differences- non-ignorable
missingness.
• How to know the non-ignorable missingness?
– Record the demographic characteristics of
noncompliance
– Compare compliers and noncompliers in
these characteristics
Phases in new drug testing in US
• Phase I: Researchers test a new drug or treatment in a
small group of people for the first time to evaluate its
safety, determine a safe dosage range, and identify side
effects.
• Phase II: The drug or treatment is given to a larger group
of people to see if it is effective and to further evaluate its
safety.
• Phase III: The drug or treatment is given to large groups of
people to confirm its effectiveness, monitor side effects,
compare it to commonly used treatments, and collect
information that will allow the drug or treatment to be used
safely.
• Phase IV: Studies are done after the drug or treatment has
been marketed to gather information on the drug's effect in
various populations and any side effects associated with
long-term use.